Summary Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease with few survivors. Progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of tumor-promoting inflammation in PDA are poorly understood. Dectin-1 is a member of the C-type Lectin family of pattern recognition receptors and is required for the innate immune response to fungal pathogens. However, Dectin-1 does not have an established role in sterile inflammation or in promoting oncogenesis. Non-pathogen- derived Dectin-1 ligands have not been well-characterized. Our preliminary data showed that Dectin-1 in highly expressed in both the inflammatory and epithelial compartments in PDA in mice and humans. Moreover, Dectin-1 ligation accelerated PDA development whereas Dectin-1 deletion was protective. Further, we discovered that Galectin-9, a lectin with affinity for ?-galactosides, is ubiquitous within the PDA tumor microenvironment and avidly ligates Dectin-1. Mechanistically, we found that Dectin-1 signaling in tumor-associated macrophages (TAMs) induces their reprogramming into immune-suppressive M2-like macrophages leading to Th2 and Treg differentiation of CD4+ T cells in vivo. Based on these data, we postulate that Dectin-1 ligation of Galectin-9 is a pivotal switch which drives immune-suppression in the pancreatic TME. In Aim 1 we will determine the consequences of Dectin-1 activation in PDA and test whether targeting Dectin-1 or Galectin-9 are protective and extend survival in diverse murine models of PDA. We will also determine the specific compartment (epithelial vs inflammatory) in which Dectin-1 signaling is oncogenic. In Aim 2 we will test our overriding hypothesis is that Dectin-1 signaling in myeloid cells induces the differential expansion of immune-suppressive macrophage subsets which have the proclivity to generate pro-tumorigenic T cells leading to tumor-permissive anergy. We also will delineate the biochemical mechanism of Dectin-1-dependant adaptive immune anergy in PDA and test our translational hypothesis that targeting Dectin-1 will have synergistic efficacy with checkpoint-receptor directed immunotherapeutic regimens. Collectively, Aim 2 will define the cellular and biochemical mechanisms of Dectin- 1 promotion of PDA and provide guidance for the development of novel strategies for experimental therapeutics. Aim 3 will be dedicated to elucidating the immune-suppressive effects of Dectin-1 signaling in human PDA and studying the implications of the Dectin-1?Galectin-9 axis on suppression of adaptive immunity and clinico- pathologic disease features and outcome in patients. We anticipate that Dectin-1 activation via Galectin-9 is a principal driver of immune-suppressive myeloid cell programming in PDA leading to CD4+ and CD8+ T-cell anergy. We believe our work has high translational value and will suggest that Dectin-1 and Galectin-9 may be attractive targets for experimental therapy in patients. Moreover, this work is likely to have far-reaching implications for a role for Dectin-1 in other cancer subtypes and in sterile inflammation.